Immunity of Mind, Body & Soul By Boosting Strength Of Nervous System

• We were spearheading Parkinson’s Disease Cure by 2024 or before at our Life Sciences Firm RELIFE https://bit.ly/3e9jj7i using stem cell therapies, gene therapies, growth factors (like GDNF), new drugs that can reduce dyskinesia & deep brain stimulation or DBS. These are discussed in this article.
• And suddenly COVID19 struck & we have quantified the impact of COVID19 on the nervous system. The COVID impact has given us major breakthrough and we see the cure coming even sooner for all nervous system related diseases.
• The central nervous system (CNS) is highly protected in the human body.
• Yet, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the CNS, causing profound clinical complications.
• Many of the symptoms experienced by people infected with SARS-CoV-2 involve the nervous system.
• Patients complain of headaches, muscle and joint pain, fatigue and “brain fog,” or loss of taste and smell — all of which can last from weeks to months after infection.
• In severe cases, COVID-19 can also lead to encephalitis or stroke. The virus has undeniable neurological effects.
• The ACE2 (angiotensin-converting enzyme II) receptor — essential for the SARS-CoV-2 entry into the host cell — is also found in the brain.
• The virus enters the olfactory nerves via the ACE2 and migrates along the neuroepithelial route to reach the brain (as evident by the loss of smell in COVID-19 patients) & via the blood-brain barrier by binding to the ACE2 on the endothelial cells and traversing the highly selective barrier.
• The Cytokine storms associated with severe SARS-CoV-2 infection, high fever and inflammation increases the blood-brain barrier’s permeability.
• The general blood circulation and ACE2 expressed in capillary endothelium is the route to enter the brain.
• If following practices are followed the nervous system can become very resilient not just to stop the impact of COVID19 but also to dampen itty building immunity of Mind, Body & Soul.

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How SARS-CoV-2 enters the central nervous system

• The central nervous system (CNS) is highly protected in the human body. Yet, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the CNS, causing profound clinical complications. How is the CNS involved in a respiratory virus infection?
• To understand this, researchers reviewed reported case studies and identified potential brain regions that may be affected by the SARS-CoV-2 and explored the virus’s possible entry route into the brain to identify its pathogenicity.

Background

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), the respiratory illness responsible for the COVID-19 pandemic. The novel virus belongs to the coronavirus family and has infected over 109 million people and claimed over 2.4 million lives since its emergence in late December 2019 in Wuhan, China. Coronaviruses are a family of ribonucleic acid viruses that are known to cause disease in humans and animals. SARS-CoV-2 is the seventh known coronavirus to infect people, after 229E, NL63, OC43, HKU1, MERS-CoV, and the original SARS-CoV-1
• Clinicians and researchers from across the world strived to understand the SARS-CoV-2 infection. The most common symptoms are cough, fever, fatigue, and respiratory distress. Although it is predominantly a respiratory disease, neurological manifestations are also associated with it.

Evidence from other viruses

• The predecessor of SARS-CoV-2, SARS-CoV-1, infects the brain. SARS-CoV-1 has been detected in neurons, causing focal degeneration and edema.
• The MERS-CoV infects the CNS, with higher mortality rates as compared to lung infections. The neurological manifestations in these infections include delayed neurologic consequences, such as myopathy, Guillain-Barre syndrome peripheral neuropathy, and Bickerstaff brainstem encephalitis that occurred weeks after respiratory symptoms.

The clinical cases

• A COVID-19 positive patient experienced seizures, although she had no history of alcohol/drug abuse or epilepsy. In another case, the patient had an altered mental condition, and the final diagnosis was acute necrotizing encephalopathy associated with SARS-CoV-2 infection.
• Likewise, the reviewers have collated such cases that involve any of these manifestations: meningeal irritation, encephalitis with SARS-CoV-2 in the CSF, inflammation of the brain and spinal cord, ataxia (damage to the cerebellum), impaired consciousness and acute cerebrovascular diseases, encephalopathy or constant change in consciousness, etc. In the case of reduced taste and smell, the virus can disrupt the cranial nerves which may lead to chemosensory dysfunction affecting taste sensation.
• Moreover, SARS-CoV-2 may be latent in the CNS. Therefore, the reviewers bring attention to the possibility of “cured” patients suffering from neurological diseases later in time; this warrants further investigations.

Invasion of SARS-CoV-2 into the brain

• The ACE2 (angiotensin-converting enzyme II) receptor — essential for the SARS-CoV-2 entry into the host cell — is also found in the brain.
• Among possible routes of entry into the CNS, the virus may enter the olfactory nerves via the ACE2 and migrate along the neuroepithelial route to reach the brain (as evident by the loss of smell in COVID-19 patients) or via the blood-brain barrier by binding to the ACE2 on the endothelial cells and traversing the highly selective barrier, the reviewers write.
• The Cytokine storms associated with severe SARS-CoV-2 infection, high fever and inflammation may increase the blood-brain barrier’s permeability. The general blood circulation and ACE2 expressed in capillary endothelium is one possible route to enter the brain.
• The virus might also reside inside the “Trojan horse of the microbial world,” such as the resilient Acanthamoeba castellanii and other cells such as the bloodstream leukocytes, dendritic cells and myeloid cells. Through these carriers or reservoirs of the virus, it is suggested that the SARS-CoV-2 may gain entry into the CNS.

ACE2 in the brain

• The host tropism of coronaviruses is determined by the Spike (S) protein of the virus. And also the presence of the ACE2. The expression of ACE2 is high in the substantia nigra and brain ventricles, as well as both excitatory and inhibitory neurons in the middle temporal gyrus and posterior cingulate cortex. It is also present in the brain nuclei of essential cells and hypothalamic areas, Piriform cortex (associated with the sense of smell), hippocampal regions and excitatory neurons.

Significance and impact

• Though the brain is immune privileged, it is now established that SARS-CoV-2 enters brain cells. The role of vaccines in preventing and protecting the brain cells from infection is unclear. Under this purview, further studies of clinical trials along the vaccine rollout are required.
• The reviewers also recommend that because the virus can transverse into the CNS, the drugs currently used for COVID-19 treatment need to be reviewed.
• Given the heterogeneous complications within the nervous system, it is important to confirm whether patients are suffering from SARS-CoV-2 infection with neurological involvement.

Conclusion

• Mounting evidence suggests that it invades the CNS; patients show symptoms related to brain infection. It is also found in the cerebrospinal fluid (CSF). The parietal lobe and the cerebellum appear to be the likely targets of SARS-CoV-2. Further studies related to this are warranted to arrive at conclusions.
• These findings need to be considered when treating COVID-19 patients, the reviewers inform.

The Immune System & Nervous System Link

• The immune system and the nervous system maintain extensive communication, including ‘hardwiring’ of sympathetic and parasympathetic nerves to lymphoid organs. Neurotransmitters such as acetylcholine, norepinephrine, vasoactive intestinal peptide, substance P and histamine modulate immune activity. Neuroendocrine hormones such as corticotropin-releasing factor, leptin and α-melanocyte stimulating hormone regulate cytokine balance. The immune system modulates brain activity, including body temperature, sleep and feeding behavior. Molecules such as the major histocompatibility complex not only direct T cells to immunogenic molecules held in its cleft but also modulate development of neuronal connections. Neurobiologists and immunologists are exploring common ideas like the synapse to understand properties such as memory that are shared in these two systems.
• When the ancient Egyptians prepared a mummy they would scoop out the brain through the nostrils and throw it away. While other organs were preserved and entombed, the brain was considered separately from the rest of the body, and unnecessary for life or afterlife. Eventually, of course, healers and scientists realized that the three pounds of entangled neurons beneath our crania serve some rather critical functions. Yet even now the brain is often viewed as somewhat divorced from the rest of the body; a neurobiological Oz crewing our bodies and minds from behind the scenes with unique biology and unique pathologies.
• Perhaps the most commonly cited division between body and brain concerns the immune system. When exposed to foreign bacteria, viruses, tumors, and transplant tissue, the body stirs up a torrent of immune activity: white blood cells devour invading pathogens and burst compromised cells; antibodies tag outsiders for destruction. Except, that is, in the brain. Thought to be too vulnerable to host an onslaught of angry defensive cells, the brain was assumed to be protected from this immune cascade. However research reported a previously unknown line of communication between our brains and immune systems, adding to a fast-growing body of research suggesting that the brain and body are more connected than previously thought. The new work could have important implications for understanding and treating disorders of the brain.
• As early as 1921 scientists recognized that the brain is different, immunologically speaking. Outside tissue grafted into most parts of the body often results in immunologic attack; tissue grafted into the central nervous system on the other hand sparks a far less hostile response. Thanks in part to the blood-brain barrier — tightly packed cells lining the brain’s vessels that let nutrients slip by, but, for the most part, keep out unwanted invaders like bacteria and viruses — the brain was long considered “immunologically privileged,” meaning it can tolerate the introduction of outside pathogens and tissues. The central nervous system was seen as existing separately from the peripheral immune system, left to wield its own less aggressive immune defenses.
• The brain’s privilege was also considered to be due to its lack of lymphatic drainage. The lymphatic system is our body’s third and perhaps least considered set of vessels, the others being arteries and veins. Lymphatic vessels return intracellular fluid to the bloodstream while lymph nodes — stationed periodically along the vessel network — serve has storehouses for immune cells. In most parts of the body, antigens — molecules on pathogens or foreign tissue that alert our immune system to potential threats — are presented to white blood cells in our the lymph nodes causing an immune response. But it was assumed that this doesn’t occur in the brain given its lack of a lymphatic network, which is why the new findings represent a dogmatic shift in understanding how the brain interacts with the immune system.
• Working primarily with mice, researchers identified a previously undetected network of lymphatic vessels in the meninges — the membranes that surround the brain and spinal cord — that shuttle fluid and immune cells from the cerebrospinal fluid to a group of lymph nodes in the neck, the deep cervical lymph nodes. Studies had previously shown that a type of white blood cell called T-cells in the meninges are associated with significant influences on cognition and hence were curious about the role of meningeal immunity on brain function. By mounting whole mouse meninges and using neuroimaging the team noticed that T-cells were present in vessels separate from arteries and veins, confirming that the brain does in fact have a lymphatic system linking it directly the peripheral immune system. Research stumbled upon these vessels completely by serendipity.
• The newly discovered vessels — which were also identified in human samples — could explain a variety of pathophysiological conundrums, namely how the immune system contributes to neurological and psychiatric disease. But that alteration in these vessels may affect disease progression in those neurological disorders with a prominent immune component, such as multiple sclerosis, autism and Alzheimer’s disease.
• For example Multiple sclerosis (MS), at least in some cases, is thought to result from autoimmune activity in response to an infection in the central nervous system and cerebrospinal fluid. Perhaps antigens from the infectious culprit find their way to the cervical lymph nodes via the meningeal lymphatic vessels, inciting the immune response that causes MS symptoms. Alzheimer’s is thought to be caused by the build up and transmission of a protein called amyloid in the brain. It could be that the amyloid isn’t being cleared properly via these lymphatic vessels, and that somehow improving their patency might help rid the brain of the pathologic protein.
• Other research found that an injury to the central nervous system results in a strong activation of T-cells in the deep cervical lymph nodes. Study suspects that some compound may be released from the injured CNS that is transmitted to the deep cervical lymph nodes through lymphatic vessels where it activatesthe immune system. A similar scenario may be at work in other neurological conditions; that too much or too little drainage from the central nervous system to the immune system might contribute to brain disease. If so, Kipnis feels targeting the vessels with drugs, genetic manipulation and surgery are therapeutic approaches worth pursuing.
• The new findings could help to explain the initiation, maintenance, and perhaps worsening of autoimmune disorders that affect the brain; and also that in light of the new findings the textbooks might need some revising. It has become increasingly clear that the [central nervous system] is immune different rather than immune privileged.
• It’s been clear for decades that there is some kind of relationship between the brain and the immune system. Abnormal immune activity was reported in schizophrenia in the 1930s, and numerous mental and neurologic illnesses are known or thought to have an immune component. However the group identified a tangible, anatomical structure facilitating this relationship suggests that the brain and body are intimately intertwined, and that the brain is not the citadel it was once thought to be.
• A newly-discovered reflex arc mediates a process which leads to a disruption in the hormones secreted by the adrenal glands which, in turn, results in an increased susceptibility to bacterial infections. This research breaks new ground in the development of treatments to reduce the incidence of infections.
• Injuries to the brain or spinal cord, such as those caused by stroke or trauma, result in a considerable weakening of the immune system. This often leads to severe infections, such as pneumonia or urinary tract infections, which hamper nervous tissue regeneration as well as rehabilitation in affected patients. Until now, our understanding of the exact manner in which nerve tissue damage leads to infections (and which physiological parameters are responsible) has remained rudimentary at best. A team of researchers have now succeeded in deciphering this process.
• Their study was based on the premise that nerve pathways originating in the spinal cord exert a direct influence on organs involved in the immune system, such as lymph nodes and the spleen. The disruption of immune organ function does not occur as a result of this direct connection; instead, it is the result of an immune system dysregulation which affects the entire body.
• The researchers showed that the nervous system uses adrenal hormones as part of an indirect path of communication which results in the rapid breakdown of many immune cells. In a healthy body, the adrenal glands are controlled by both the nervous system and the relevant hormone control centers. Until recently, it had been assumed that a brain injury via hormonal signals results in the adrenal glands secreting cortisol, while a trauma-induced stress response results in the release of adrenaline and noradrenaline. New data shows that the disruption in the normal function of the adrenal glands is under the direct control of damaged nerve tissue. In contrast to received opinion, trauma-induced spinal cord injury initially resulted in a decrease in stress hormones and an increase in cortisol production.
• This alteration in hormone levels led to a dramatic decrease in the numbers of many immune cells, particularly affecting the precursors of T-cells and B-cells. In some cases, this resulted in a reduction of between 50 and 80 percent in the size of the spleen, thymus or lymph nodes. While experimental deactivation of the adrenal glands led to a reversal of this dramatic loss of immune cells, the mice treated in this manner remained susceptible to infections. However, an autograft of adrenal tissue, transplanted into these mice, conferred protection against infections. While the transplanted adrenals produce the hormones needed by the body, they are no longer subject to the dysfunctional nervous system control mechanisms which develop following high level spinal injury.
• The identification of this two-stage pathological reflex arc — consisting of nerve pathways between the spinal cord and the adrenal glands, as well as a hormone-mediated link with the immune system — helps to deepen our understanding of the interconnections which exist between the nervous and immune system. The discovery of this ‘immune system paralysis’ and its underlying mechanisms represents an important step on the path to improving the treatment of spinal cord injury patients. Rather than merely experiencing the more obvious symptom of motor-sensory paralysis, paraplegic patients also experience a paralysis of the immune system.
• Comprehensive analyses of patients’ cortisol and (nor)adrenaline levels have shown that they exhibit a fundamentally similar behavior to that seen in experimental studies. This suggests that treatment aimed at normalizing this neuro-endocrine reflex may prove effective in controlling the sometimes life-threatening infections associated with injuries to the central nervous system.

Coronavirus and the Nervous System

What is COVID-19?

• Coronaviruses are common causes of usually mild to moderate upper respiratory tract illnesses like the common cold, with symptoms that may include runny nose, fever, sore throat, cough, or a general feeling of being ill. However, a new coronavirus called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) emerged and spread to cause the COVID-19 pandemic.
• COVID-19, which means Coronavirus disease 2019, is an infectious disease that can affect people of all ages in many ways. It is most dangerous when the virus spreads from the upper respiratory tract into the lungs to cause viral pneumonia and lung damage leading to Acute Respiratory Distress Syndrome (ARDS). When severe, this impairs the body’s ability to maintain critical levels of oxygen in the blood stream — which can cause multiple body systems to fail and can be fatal.

What do we know about the effects of SARS-CoV-2 and COVID-19 on the nervous system?

• Much of the research to date has focused on the acute infection and saving lives. These strategies have included preventing infection with vaccines, treating COVID-19 symptoms with medicines or antibodies, and reducing complications in infected individuals.
• Research shows the many neurological symptoms of COVID-19 are likely a result of the body’s widespread immune response to infection rather than the virus directly infecting the brain or nervous system. In some people, the SARS-CoV-2 infection causes an overreactive response of the immune system which can also damage body systems. Changes in the immune system have been seen in studies of the cerebrospinal fluid, which bathes the brain, in people who have been infected by SARS-CoV-2. This includes the presence of antibodies — proteins made by the immune system to fight the virus — that may also react with the nervous system. Although still under intense investigation, there is no evidence of widespread viral infection in the brain. Scientists are still learning how the virus affects the brain and other organs in the long-term. Research is just beginning to focus on the role of autoimmune reactions and other changes that cause the set of symptoms that some people experience after their initial recovery. It is unknown if injury to the nervous system or other body organs cause lingering effects that will resolve over time, or whether COVID-19 infection sets up a more persistent or even chronic disorder.

What are the immediate (acute) effects of SARS-CoV-2 and COVID-19 on the brain?

• Most people infected with SARS-CoV-2 virus will have no or mild to moderate symptoms associated with the brain or nervous system. However, most hospitalized patients do have symptoms related to the brain or nervous system, most commonly including muscle aches, headaches, dizziness, and altered taste and smell. Some people with COVID-19 either initially have, or develop in the hospital, a dramatic state of confusion called delirium. Although rare, COVID-19 can cause seizures or major strokes. Muscular weakness, nerve injury, and pain syndromes are common in people who require intensive care during infections. There are also very rare reports of conditions that develop after SARS-CoV-2 infection, as they sometimes do with other types of infections. These disorders of inflammation in the nervous system include Guillain-Barré syndrome (which affects nerves), transverse myelitis (which affects the spinal cord), and acute necrotizing leukoencephalopathy (which affects the brain).

Bleeding in the brain, weakened blood vessels, and blood clots in acute infection

• The SARS-CoV-2 virus attaches to a specific molecule (called a receptor) on the surface of cells in the body. This molecule is concentrated in the lung cells but is also present on certain cells that line blood vessels in the body. The infection causes some arteries and veins — including those in the brain — to become thin, weaken, and leak. Breaks in small blood vessels have caused bleeding in the brain (so-called microbleeds) in some people with COVID-19 infection. Studies in people who have died due to COVID-19 infection show leaky blood vessels in different areas of the brain that allow water and a host of other molecules as well as blood cells that are normally excluded from the brain to move from the blood stream into the brain. This leak, as well as the resulting inflammation around blood vessels, can cause multiple small areas of damage. COVID-19 also causes blood cells to clump and form clots in arteries and veins throughout the body. These blockages reduce or block the flow of blood, oxygen, and nutrients that cells need to function and can lead to a stroke or heart attack.
• A stroke is a sudden interruption of continuous blood flow to the brain. A stroke occurs either when a blood vessel in the brain becomes blocked or narrowed or when a blood vessel bursts and spills blood into the brain. Strokes can damage brain cells and cause permanent disability. The blood clots and vascular (relating to the veins, capillaries, and arteries in the body) damage from COVID-19 can cause strokes even in young healthy adults who do not have the common risk factors for stroke.
• COVID-19 can cause blood clots in other parts of the body, too. A blood clot in or near the heart can cause a heart attack. A heart attack orInflammation in the heart, called myocarditis, can cause heart failure, and reduce the flow of blood to other parts of the body. A blood clot in the lungs can impair breathing and cause pain. Blood clots also can damage the kidneys and other organs.
• Low levels of oxygen in the body (called hypoxia) can permanently damage the brain and other vital organs in the body. Some hospitalized individuals require artificial ventilation on respirators. To avoid chest movements that oppose use of the ventilator it may be necessary to temporarily “paralyze” the patient and use anesthetic drugs to put the individual to sleep. Some individuals with severe hypoxia require artificial means of bringing oxygen into their blood stream, a technique called extra corporeal membrane oxygenation (ECMO). Hypoxia combined with these intensive care unit measure generally cause cognitive disorders that show slow recovery.
• Diagnostic imaging of some people who have had COVID-19 show changes in the brain’s white matter that contains the long nerve fibers, or “wires,” over which information flows from one brain region to another. These changes may be due to a lack of oxygen in the brain, the inflammatory immune system response to the virus, injury to blood vessels, or leaky blood vessels. This “diffuse white matter disease” might contribute to cognitive difficulties in people with COVID-19. Diffuse white matter disease is not uncommon in individuals requiring intensive hospital care but it not clear if it also occurs in those with mild to moderate severity of COVID-19 illness.

What is the typical recovery from COVID-19?

• Fortunately, people who have mild to moderate symptoms typically recover in a few days or weeks. However, some people who have had only mild or moderate symptoms of COVID-19 continue to experience dysfunction of body systems — particularly in the lungs but also possibly affecting the liver, kidneys, heart, skin, and brain and nervous system — months after their infection. In rare cases, some individuals may develop new symptoms (called sequelae) that stem from but were not present at the time of initial infection. People who require intensive care for Acute Respiratory Distress Syndrome, regardless of the cause, usually have a long period of recovery. Individuals with long-term effects, whether following mild or more severe COVID-19, have in some cases self-identified as having “long COVID” or “long haul COVID.” These long-term symptoms are included in the scientific term, Post Acute Sequelae of SARS-CoV-2 Infection (PASC).

What are possible long-term neurological complications of COVID-19?

• Researchers are following some known acute effects of the virus to determine their relationship to the post-acute complications of COVID-19 infection. These post-acute effects usually include fatigue in combination with a series of other symptoms. These may include trouble with concentration and memory, sleep disorders, fluctuating heart rate and alternating sense of feeling hot or cold, cough, shortness of breath, problems with sleep, inability to exercise to previous normal levels, feeling sick for a day or two after exercising (post-exertional malaise), and pain in muscle, joints, and chest. It is not yet known how the infection leads to these persistent symptoms and why in some individuals and not others.

Nerve damage, including peripheral neuropathy

• Some symptoms experienced by some people weeks to months after COVID infection suggest the peripheral nervous system, the vast communication network that sends signals between the central nervous system (the brain and spinal cord) and all other parts of the body, is impaired. Peripheral nerves send many types of sensory information to the central nervous system (CNS), such as a message that the feet are cold. They also carry signals from the CNS to the rest of the body, including those that control voluntary movement. Nerve dysfunction is also a known complication in those with critical care illness such as the acute respiratory distress syndrome.

Symptoms of peripheral neuropathy vary depending on the type of nerves — motor, sensory, or autonomic — that are damaged.

• Motor nerves control the movement of all muscles under conscious control, such as those used for walking, grasping things, or talking. Damage to the motor nerves can cause muscle weakness and cramps.
• Sensory nerves carry messages from our sense of touch, sight, hearing, taste, and smell. Sensory nerves transmit information such as the feeling of a light touch, temperature, or pain. The symptoms of sensory nerve damage can include loss of sense of touch, temperature, and pain or a tingling sensation.
• Autonomic nerves control organs to regulate activities that people do not control consciously, such as breathing, digestion, and heart and gland functions. Common symptoms include excess or absence of sweating, heat intolerance, and drop in blood pressure upon standing. Postural orthostatic tachycardia syndrome (also known as POTS) can increase heart rate when standing up and cause such symptoms as lightheadedness (or fainting) or difficulty concentrating.

Fatigue and post-exertional malaise.

• The most common persistent symptom weeks and months after COVID-19 infection is fatigue. The fatigue is similar to what one experiences with many viral infections such as the flu. The sense of fatigue can be brought on by both physical and mental activity. Some people are unable to return to work or school after COVID-19 due to fatigue, while others find it extremely difficult to accomplish their normal level of activity. Tasks such as walking the dog or going shopping can cause extreme tiredness and fatigue; some people can’t carry out everyday activities without feeling pain or tiredness. COVID-related complications such as depressed heart, lung, or kidney function, poor sleep, or muscle deconditioning are known to cause fatigue and affect the ability to exercise. Fatigue is very common in most inflammatory conditions. The cause(s) of fatigue in many of those suffering weeks and months after COVID-19 is not known.
• Post-exertional malaise (PEM) is a condition in which otherwise usual activities are followed by a period of very severe fatigue and sense of feeling sick. PEM can occur with a delay after the activity, but can last for days thereafter.

Cognitive impairment/altered mental state

• People with severe acute COVID-19 illness may develop confusion, delirium, and a depressed level of consciousness. Those suffering from post-acute sequelae of COVID-19 frequently have difficulty concentrating and memory problems, sometimes called “brain fog.” This impairment is a common symptom in those with severe fatigue of any cause. A variety of immune, metabolic, or blood vessel abnormalities or drug effects can contribute to the dramatic effects on cognitive function in the acute infection. Whether these also underlie the problems experienced weeks or months after mild or moderate illness is not known.

Muscle, joint, and chest pain

• Some people continue to report pain in a muscle or group of muscles (myalgia), aching joints, and fatigue after recovering from the initial course of the virus. Persistent muscle pain and chest pain is commonly reported by persons recovering from ARDS, but is now being reported by those who had a mild or moderate infectious illness. Some individuals also have a sense of shortness of breath despite testing normal on pulmonary function tests.

Prolonged/lingering loss of smell (anosmia) or taste

• Some people who have had COVID-19 may lose their sense of taste or smell, or the sensation of flavor. The loss of sense of taste or smell is characteristic of COVID-19 because the SARS-CoV-2 virus infects the tissue that forms the lining in the nose. The virus has been found to target certain cells in the nose that support the nerve cells. Those nerve cells detect odors and send that information to the brain. Damage to these supporting cells can cause smell or taste loss that can continue for weeks or months as these cells repair themselves or are replaced by new cells. During the recovery period some odors may smell different — even sometimes unpleasant or foul — than people remeber prior to being infected.

Persistent fevers and chills

• Some people who recover from their acute (short-term) infection continue to have on-and-off fever, along with chills and body ache. Some people have a high, prolonged fever after the infection is gone, which might contribute to the sense of fatigue. In some instances, people who recover from the initial infection may have temperature dysregulation, in which it’s difficult for the body to keep a normal temperature.

Prolonged respiratory effects and lung damage

• COVID-19 is primarily a respiratory disease that can seriously affect the lungs during and after the infection. Some people with the disease have breathing difficulties and some require supplemental oxygen support or mechanical ventilation via a respirator. The disease also can damage the muscles that help us breathe. Lung injury can cause low blood oxygen and brain hypoxia, which occurs when the brain isn’t getting enough oxygen. This can lead to cognitive impairment, seizures, stroke, and permanent damage to the brain and other organs. Results from several studies show that, even in people who have had mild-to-moderate infection, the effects of COVID-19 can persist in the lungs for months. Some people develop pneumonia after their acute illness has passed. Several people need pulmonary (lung) rehabilitation to rebuild their lung function. Studies show several people who had the infection, particularly those who had a more severe course of illness, also develop scarring of the lung and permanent lung dysfunction.

Headaches

• Headaches are often among the many symptoms that can accompany infection from the coronavirus. Some people continue to have mild to serious headaches sometimes for weeks after recovery. The sensation of pressure is different from a migraine, which may be brought on by stress. The headaches may be infrequent or occur chronically (some people report having daily headache).

Sleep disturbances

• Some people with long-term neurological effects from the SARS-CoV-2 infection report having trouble falling asleep or staying asleep (insomnia), excessive daytime sleepiness (hypersomnia), unrefreshing sleep, and changes in sleep patterns. It may be difficult for some people to wake up and fall asleep at their regular times. Depression, anxiety, and post-traumatic stress disorder (PTSD) can negatively affect sleep. Sleep disorders can contribute to fatigue and cognitive troubles. Some people report an increase in pain, headache, and stress because of lack of sleep. Continued loss of sleep also negatively affects attention and mood.

Anxiety, depression, and stress post-COVID

• The outbreak of COVID-19 is stressful for many people. People respond to stress in different ways and it is normal to experience a range of emotions, including fear, anxiety, and grief. Being isolated from others during the infection, the real risk of death, and the stress of hospitalization and critical care can trigger post-traumatic stress disorder. In addition, given the contagious nature of COVID-19, the individual is often not the only affected person in the family or circle of friends, some of whom may even have died. Some people may develop a mood or anxiety disorder.

How do the long-term effects of SARS-CoV-2 infection/COVID-19 relate to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)?

• Some of the symptom clusters reported by people still suffering months after their COVID-19 infection overlap with symptoms described by individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). People with a diagnosis of ME/CFS have wide-ranging and debilitating effects including fatigue, PEM, unrefreshing sleep, cognitive difficulties, postural orthostatic tachycardia, and joint and muscle pain. Unfortunately, many people with ME/CFS do not return to pre-disease levels of activity. The cause of ME/CFS is unknown but many people report its onset after an infectious-like illness. Rest, conserving energy, and pacing activities are important to feeling better but don’t cure the disease. Although the long-term symptoms of COVID-19 may share features with it, ME/CFS is defined by symptom-based criteria and there are no tests that confirm an ME/CFS diagnosis.
• ME/CFS is not diagnosed until the key features, especially severe fatigue, post-exertional malaise, and unrefreshing sleep, are present for greater than six months. It is now becoming more apparent that following infection with SARS-CoV-2/COVID-19, some individuals may continue to exhibit these symptoms beyond six months and qualify for an ME/CFS diagnosis. It is unknown how many people will develop ME/CFS after SARS-CoV-2 infection. It is possible that many individuals with ME/CFS, and other disorders impacting the nervous system, may benefit greatly if research on the long-term effects of COVID-19 uncovers the cause of debilitating symptoms including intense fatigue, problems with memory and concentration, and pain.

Am I at a higher risk if I currently have a neurological disorder?

• Much is still unknown about the coronavirus but people having one of several underlying medical conditions may have an increased risk of illness. However, not everyone with an underlying condition will be at risk of developing severe illness. People who have a neurological disorder may want to discuss their concerns with their doctors.

Because COVID-19 is a new virus, there is little information on the risk of getting the infection in people who have a neurological disorder. People with any of these conditions might be at increased risk of severe illness from COVID-19:

• Cerebrovascular disease
• Stroke
• Obesity
• Dementia
• Diabetes
• High blood pressure

There is evidence that COVID-19 seems to disproportionately affect some racial and ethnic populations, perhaps because of higher rates of pre-existing conditions such as heart disease, diabetes, and lung disease. Social determinants of health (such as access to health care, poverty, education, ability to remain socially distant, and where people live and work) also contribute to increased health risk and outcomes.

Can COVID-19 cause other neurological disorders?

• In some people, response to the coronavirus has been shown to increase the risk of stroke, dementia, muscle and nerve damage, encephalitis, and vascular disorders. Some researchers think the unbalanced immune system caused by reacting to the coronavirus may lead to autoimmune diseases, but it’s too early to tell.

Anecdotal reports of other diseases and conditions that may be triggered by the immune system response to COVID-19 include para-infectious conditions that occur within days to a few weeks after infection:

• Multi-system infammatory syndrome — which causes inflammation in the body’s blood vessels
• Transverse myelitis — an inflammation of the spinal cord
• Guillain-Barré sydrome (sometimes known as acute polyradiculoneuritis) — a rare neurological disorder which can range from brief weakness to nearly devastating paralysis, leaving the person unable to breathe independently
• Dysautonomia — dysfunction of the autonomic nerve system, which is involved with functions such a breathing, heart rate, and temperature control
• Acute disseminating encephalomyelitis (ADEM) — an attack on the protective myelin covering of nerve fibers in the brain and spinal cord
• Acute necrotizing hemorrhagic encephalopathy — a rare type of brain disease that causes lesions in certain parts of the brain and bleeding (hemorrhage) that can cause tissue death (necrosis)
• Facial nerve palsies (lack of function of a facial nerve) such as Bell’s Palsy
• Parkinson’s disease-like symptoms have been reported in a few individuals who had no family history or early signs of the disease

Routes of reaching the nervous system and possible pathophysiology

• For a given virus, the ability to infect certain cells, tissues, or even species while not affecting others is referred to as viral tropism. This viral tropism, allowing a virus to replicate in and affect certain body tissues, would then lead to the symptomatic presentation of that virus. A major factor that dictates this tissue selectivity, is the virus’s ability to bind and take over specific host cell surface receptors. Recent research on SARS-CoV-2 has shown that similarly to SARS-CoV, this virus can invade tissues by binding to the angiotensin-converting enzyme 2 (ACE2) receptor on certain host cells (Fig. 1 A) . This binding is mediated by the spike protein found on the surface of SARS-CoV-2 and was found to have up to 20 times the binding affinity of SARS-CoV . While its mRNA can be found in virtually all body tissues, the ACE2 receptor is mostly expressed in lung alveolar epithelial cells, small intestine enterocytes, vascular endothelial cells, in addition to airway epithelial cells, and kidney cells. More recently, it was reported that brain also expresses ACE2 receptors on glial cells and neurons and this is most prominent in the brainstem, the paraventricular nucleus (PVN), nucleus tractus solitarius (NTS), and the rostral ventrolateral medulla which all play a role in cardiovascular regulation.

• On the other hand, viral tissue invasion does not solely rely on the presence of certain receptors and the ability to hijack them. Recent studies on the novel coronavirus have shown that, like its predecessors, a substantial part of its symptomatology can be explained by the cytokine storm it triggers, leading to a systemic inflammatory response syndrome (SIRS) or SIRS-like phenomenon (Fig 1 B). This inflammation is mediated by interleukins (IL-6 and IL-8) released by monocytes and macrophages to stimulate other monocytes and both B and T lymphocytes, in addition to monocyte chemoattractant protein-1 (MCP-1), a chemokine responsible for the transmigration of the monocytes across the blood-brain barrier (BBB). Thus, this can then lead to the inflammation of the BBB and increase its permeability which facilitates the passage of more inflammatory cytokines and chemokines into the brain and can exacerbate the neuroinflammation and neurological symptoms experienced by the patient.
• Additionally, during previous coronavirus epidemics (SARS-CoV and MERS-CoV), animal studies on transgenic mice showed that both of these viruses were able to reach the brain when introduced intranasally. Research reported that viral antigens could be detected in all brain regions, only 7 days after viral nasal inhalation in mice. This brain entry is possibly mediated by the olfactory nerves and olfactory bulb which are conveniently accessible by the virus from its intranasal location. Interestingly, mice experiments with ablation of the olfactory nerves have shown a substantial decrease in coronavirus (Mouse Hepatitis Virus) neuroinvasion.
• Finally, it is important to mention that the virus can also cause CNS damage and neurological symptoms without invading the brain itself. As respiratory viruses invade the lungs and cause inflammation, this leads to alveolar and lung tissue damage. Inflammation and edema affect the oxygen exchange that happens at the alveolar-capillary interface leading to hypoxemia and subsequently brain hypoxia with vasodilation, hyperemia and brain edema (Fig. 2 ). This would then manifest itself starting with headaches and, if kept unchecked, could cause a change in the level of consciousness and even coma. Being a respiratory virus itself, SARS-CoV-2 has been shown to cause significant hypoxemia in many of the patients and hence, this possible pathway of brain injury remains a factor in its symptomatic profile.

Neuroinvasive potentials of coronavirus and its role in respiratory failure

• There is still a debate regarding the exact role of brainstem invasion by the virus in causing respiratory failure in COVID-19 patients. Research (2020) has suggested that SARS-CoV-2 can enter the brain, and it might be the cause of the respiratory failure in patients with COVID-19. On the other hand, another study has reported that respiratory failure alone does not suggest central nervous system invasion by SARS-CoV-2. Research relied on certain points to support his conclusion; patients with pneumonia typically develop hypoxic, or type 1 respiratory failure, with low CO2 levels and a raised respiratory rate, while brain failure typically leads to type 2 respiratory failure and involves low oxygen, high CO2 and reduced respiratory rate. Research mentioned that these manifestations of type 2 respiratory failure were not reported to any great degree in any of the case series of patients from China. Research also stated that if the neuroinvasion of the virus would be the cause of respiratory failure, the virus should be detected in the cerebrospinal fluid of these patients .

Among COVID-19 patients, are smokers at higher risk for brain infection?

• Recently, research raised the question of nicotine associated neurological comorbidity in COVID19 patients depending on published evidence that the viral target receptor ACE2 is expressed in the brain and functionally interacts with nAChRs. They considered neural cells and astrocytes (especially in the hypothalamus and brain stem) more prone to infection in smokers because nicotine stimulation of the nAChR was found to increase ACE2 expression within them (Fig. 3 ). ACE2 signaling pathway is believed to counteract oxidative stress and neuroinflammation, thus, disruption in ACE balance can lead to neurodegeneration of dopaminergic neurons or impairment in cholinergic pathways which might participate in the progression of Alzheimer’s disease.

• We believe that this association between smoking and COVID-19 neurological manifestations, if proven, might be of great impact, since all the people worldwide are currently at high risk of being exposed to smoking and COVID-19 infection. Hence, more studies are strongly encouraged in this regard.

COVID-19 associated neurological manifestations

• Data on COVID-19 is not yet complete or comprehensive as we are still in the midst of the active pandemic. However, early research from Wuhan, China reported that the most common symptoms that appeared among patients with COVID-19 included fever (98.6 %), fatigue (69.6 %), and a dry cough (59.4 %). While these symptoms are typical of respiratory viruses, other sources additionally reported neurological symptoms and manifestation in up to 36.4 % of 814 retrospectively studied COVID19 patients (Table 1 ).

Acute transverse myelitis

• Acute transverse myelitis, also referred to just as transverse myelitis (TM), is a rare neurological disturbance consisting of an inflammation of the spinal cord. Patients with TM may present with sensory changes, weakness and autonomic dysfunctions. While no preceding infection was found in some of the reported cases, transverse myelitis is usually associated with common viral infections such as Varicella Zoster (VZV), Herpes viruses (HSV-2 and Cytomegalovirus) and enteroviruses . In February of 2020, in Wuhan, China, an elderly patient presented to the hospital with fever and fatigue with no previous contact with COVID-19 patients. He was found to have COVID-19 based on PCR tests of his nasopharyngeal secretions. After a week of hospitalization, he developed lower extremity weakness and paresthesia progressing to paralysis, along with urinary and bowel incontinence. He was diagnosed with post-infectious acute transverse myelitis. IgM antibodies of the most common infectious organisms associated with TM (Mycoplasma pneumoniae, Ebstein-Barr Virus, and Cytomegalovirus) were negative, and it was concluded that the cause of his post-infectious TM was SARS-CoV-2 virus. Although this case report provides a strong basis for COVID-19 associated transverse myelitis, it is worth noting that CSF serological tests and a spinal cord MRI were not performed .
• In addition, research reported a case of a 60-year-old COVID-19 patient who developed multifocal transverse myelitis 10 days after developing COVID-19 pneumonia symptoms. T2-weighted MRI of the spine showed evidence of transverse myelitis . All work-up tests for the typical viral causes of transverse myelitis came back negative. The patient was able to improve on multiple empiric treatments, such as intravenous immunoglobulins, steroids, and antivirals.

Viral encephalitis and meningitis

• Encephalitis and meningitis can be caused by viruses like Herpes Simplex Virus, Rabies and others . They can present with an acute onset fever, nausea and vomiting along with neurological manifestations; including headache, altered level of consciousness, behavioral disturbances, seizures, photophobia, or hemiparesis . While treatable in most cases, early detection and appropriate treatment are important to avoid the development of long-term and more severe complications. If left untreated, mortality rates can reach up to 70 % as reported in certain cases of herpes related encephalitis and meningitis . Recently, during the COVID-19 pandemic, a 24-year-old man was transferred to the University of Yamanashi Hospital in Japan after being found unconscious in his home. He reported typical signs of meningitis and encephalitis. CSF was found to be positive for SARS-CoV-2, while his nasopharyngeal secretions were negative. This case provides evidence of the neuroinvasive potential of SARS-CoV-2 and its role in the development of meningitis/encephalitis. Besides, it also raises the concern of having patients with COVID-19 that have negative nasopharyngeal swabs for the virus. Another case of COVID-19-associated encephalitis was reported by researchers in Turkey . A 35-year-old female patient was found to be positive for SARS-CoV-2 after undergoing a left anterior temporal lobectomy for refractory seizures. This patient’s pre-operative magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) result were suggestive of high-grade glioma, however, a biopsy taken during her surgery was nondiagnostic. Knowing that encephalitis may often be indistinguishable from other CNS pathology on MRS , Efe et al. thus reported that their patient could have a case of COVID-19-associated encephalitis mimicking a glioma.
• Moreover, Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) was reported in a COVID-19 patient. MERS is an encephalitis/encephalopathy syndrome that is associated with viral infections . This was the first reported case of MERS associated with coronavirus infection, which adds to the expanding list of differential diagnoses to be considered in a COVID-19 patient with neurological signs, most notably; cerebellar ataxia and disturbance in consciousness.

Infectious toxic encephalopathy

• Infectious toxic encephalopathy, also known as acute toxic encephalitis, is a rare type of reversible brain dysfunction syndrome associated with cerebral edema, with no evidence of inflammation on cerebrospinal fluid analysis. Metabolic disorders, systemic toxemia, and hypoxia are considered contributing factors during the process of acute infection. It has a wide clinical presentation. Patients with a mild form of the disease may develop headache, dysphoria, or delirium. While more severe forms may lead to disorientation, paralysis, loss of consciousness and even coma. Acute viral infection is a known cause of this disease. COVID-19 infection has been suggested as a cause of this disease depending on many findings. First, patients with COVID-19 may suffer from severe hypoxia and viremia , which might eventually lead to toxic encephalopathy. Moreover, around 40 % of patients with COVID-19 develop neurological symptoms and other brain dysfunction symptoms . Added to that, brain edema has been detected in autopsy studies of brain tissue of COVID-19 patients . Collectively, these proposals provide evidence that COVID-19 could cause infectious toxic encephalopathy, although more detailed researches are still required.

Acute hemorrhagic necrotizing encephalopathy

• Acute Hemorrhagic Necrotizing Encephalopathy (ANE) occurs most commonly in the pediatric age group but reported to be in adults as well. Characteristic radiological features include multiple symmetric lesions with thalamic involvement. Cerebral white matter, brain stem, and cerebellum are other reported areas to be involved.
• Acute necrotizing encephalopathy (ANE) is a rare complication of viral infections (including influenza viruses). Intracranial cytokine storms, with subsequent blood-brain barrier breakdown, is the most accepted theory behind ANE after viral infections. Recent evidence showed that patients with severe COVID-19 might have a cytokine storm syndrome.
• Researchers were the first to report a case of ANE in a COVID-19 patient.
• A female in her fifties presented with a 3-day history of fever, cough, and altered mental status. Laboratory work-up was negative for influenza, with the diagnosis of COVID-19 made by detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) PCR. CSF bacterial culture showed no growth after 3 days, and tests for herpes simplex virus 1 and 2, varicella-zoster virus, and West Nile virus were negative. Testing for the presence of SARS-CoV-2 in the CSF was unable to be performed. CT scan demonstrated symmetric hypoattenuation within the bilateral medial thalami, and CT angiogram and CT venogram were negative. Brain MRI showed hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions. These imaging findings were consistent with ANE and they concluded that ANE was caused by SARS-CoV2. The researchers reported that the patient was treated by intravenous immunoglobulin but high-dose steroids were not initiated due to concern for respiratory compromise. More recently, researchers reported another case of ANE in a 53-year-old COVID-19 patient with aplastic anemia. The patient present 10 days after onset of symptoms and was shown to have swelling in the brainstem on CT scan. Brain MRI showed multiple symmetric hemorrhagic lesions in the brainstem and different nuclei. The patient died 8 days after hospital admission.

Leukoencephalopathy

• Leukoencephalopathy is the name given to the group of diseases that affect the white matter of the central nervous system . Since the beginning of the COVID-19 pandemic, many reports have showed radiological evidence of white matter injury in patients with SARS-CoV-2 infections. Researchers first reported a case of COVID-19-associated leukoencephalopathy in a 59 year-old patient that deteriorated 16 days after developing COVID-19 symptoms. MRI and CT of the brain revealed diffuse white matter lesions in addition to micro-hemorrhages in the corpus callosum. However, the authors did not provide a solid evidence that leukoencephalopathy was specifically due to the COVID-19 infection . Researchers reported 6 COVID-19 patients who showed symmetric T2 FLAIR hyperintense signal with restricted diffusion in the deep white matter, and sparing of the subcortical U-fibers on brain MRI . The researchers concluded that hypoxemia experienced by COVID-19 patients was the contributing factor for the development of delayed post-hypoxic leukoencephalopathy. More recently, researchers also reported similar radiological features in 11 COVID-19 patients. Although it is mandatory to rule out other etiologies in these critical patients, such as hemorrhagic encephalopathy, sepsis-associated encephalopathy, posterior reversible encephalopathy syndrome in addition to other toxic and metabolic causes, leukoencephalopathy should be considered in COVID-19 patients.

Acute disseminated encephalomyelitis (ADEM)

• Acute Disseminated encephalomyelitis (ADEM) is an autoimmune demyelinating disease of the CNS characterized by a sudden and widespread inflammation. It affects mainly children and younger adults, and it is usually triggered by viral infections, but unlike viral encephalitis, it is not due to viral neuroinvasion. No cases of ADEM in patients with COVID-19 have been reported in the literature yet. However, there is a case of a 15-year old boy that presented to the Children’s Hospital of Buffalo with signs and symptoms of ADEM while also reporting a history of an upper respiratory tract infection a week before. This patient was given a presumed diagnosed of ADEM (MS could not be ruled out) and was found to have Human Coronavirus OC43 (HCoV−OC43) in his CSF and nasopharyngeal secretions by RT-PCR. This was the first reported case of coronavirus-associated demyelinating disease in a pediatric patient. While SARS-CoV-2 is not yet associated with such cases, HCoV−OC43 is a member of the beta-coronavirus family to which SASR-CoV-2 also belongs. In addition, the two viruses were shown to be closely related phylogenetically and are two of the only seven known human coronaviruses.

Acute cerebrovascular disease

• Although we have evidence that respiratory-related infections are an independent risk factor for acute cerebrovascular events, evidence specific to SARS-CoV-2 infection is still far from conclusive. Strokes were reported to have an incidence close to 2% in hospitalized patients with COVID-19.
• One of the early studies in this field was done by researchers on experimental mouse models and suggested that influenza virus can aggravate ischemic brain injury via triggering a cytokine cascade and can increase the risk of cerebral hemorrhage after treatment with tissue-type plasminogen activator. The infection of CoV, especially SARS-CoV-2, has been widely reported to cause cytokine storm syndromes, which may be one of the factors that CoV causes acute cerebrovascular disease. In addition, critically ill patients with severe SARS-CoV-2 infections often show elevated levels of d-dimer and severe platelet reduction, which may render these patients prone to acute cerebrovascular events.
• Interestingly, several recent reports showed that COVID-19 patients have a propensity to develop a hypercoagulable state. A brief report of three COVID-19 patients, who were young (mean age of 34 years) and previously healthy, with only one of the three having a risk factor for hypercoagulability (oral contraceptives) eventually developed cerebral venous thrombosis following their infection. In addition, a retrospective cohort study in New York City, showed that COVID-19 patients had higher National Institutes of Health Stroke Scale scores at admission, in addition to higher peak d-dimer values and a significantly higher mortality rate when compared with non-infected patients with strokes.

Other reported neurological manifestation

• Researchers published their observational study on 58 patients about neurologic features in severe SARS-CoV-2 infection; they reported agitation was present in 40 patients (69 %), diffuse corticospinal tract signs, including hyperreflexia, bilateral extensor plantar reflexes and ankle clonus, were present in 39 patients (67 %). A total of 26 of 40 patients were noted to have confusion according to the Confusion Assessment Method for the ICU and 15 of 45 (33 %) had a dysexecutive syndrome consisting of disorientation, inattention, or poorly organized movements in response to command.

Neuro-investigations

Radiology

• In addition to the previously mentioned imaging findings of COVID-19 patients with neurological complications, Helms et al. reported that 13 patients underwent Magnetic resonance imaging (MRI) of the brain because of unexplained encephalopathic features. Leptomeningeal enhancement was noted in 8 patients. 3 patients had radiological findings of stroke as the following: 2 patients had a small acute ischemic stroke with focal hyperintensity on diffusion-weighted imaging and an overlapping decreased apparent diffusion coefficient, and 1 patient had a subacute ischemic stroke with superimposed increased diffusion-weighted imaging and apparent diffusion coefficient signals. Interestingly, these patients with documented stroke on imaging were asymptomatic with no neurological manifestations, making the neurological course of the disease unpredictable and choosing the appropriate time to proceed with neurological imaging more challenging. To note, Bilateral frontotemporal hypoperfusion was noted in all 11 patients who underwent perfusion imaging.

Electroencephalography

• Although there are no other reports on electroencephalography findings in COVID-19 patients, it is worth mentioning that Helms et al. reported in their paper that in the 8 patients who underwent electroencephalography, only nonspecific changes were detected; and only one patient had diffuse bifrontal slowing consistent with encephalopathy. Similarly, Filatov et al. (2020) reported EEG findings of bilateral slowing and focal slowing in the left temporal region with sharply countered waves in patients with COVID-19 associated encephalopathy.

Cerebrospinal fluid (CSF) studies

• Researchers reported that CSF samples obtained from 7 patients were all negative for SARS-CoV-2 and none showed cells. However, examination of CSF samples revealed oligoclonal bands were present in 2 patients, with an identical electrophoretic pattern in serum. Protein and IgG levels were elevated in 1 patient. These findings might support the theory that the SARS-CoV-2 can cause neurologic manifestations indirectly, probably by triggering a reaction, rather than by direct invasion of the nervous system, although CSF was found to be positive for SARS-CoV-2 in another report.

Does the COVID-19 vaccine cause neurological problems?

• Almost everyone should get the COVID-19 vaccination. It will help protect you from getting COVID-19. The vaccines are safe and effective and cannot give you the disease. Most side effects of the vaccine may feel like flu and are temporary and go away within a day or two. In early vaccine development, there were extremely rare reports of unexplained neurological illness following COVID-19 vaccination, but regulators found no evidence the vaccines caused the illness. The U.S. Food and Drug Administration (FDA) continues to investigate any report of adverse consequences of the vaccine and none have appeared as of yet. Consult your primary care doctor or specialist if you have concerns regarding any pre-existing known allergic or other severe reactions and vaccine safety. Scientists are studying the risk to benefit ratio of the vaccine in someone who previously developed Guillain Barré syndrome after a vaccination. The general sense is the COVID-19 vaccine is safe in individuals whose Guillain-Barré syndrome was not associated with a previous vaccination.

Preparedness for People with Parkinson’s

• During the pandemic it has become clear that severe acure respiratory syndrome coronavirus (SARS-CoV-2) causes not just respiratory disease, but can affect multiple organs and tissues. Of note is the involvement of the CNS and PNS, and the fact that this involvement is independent from the severity of the respiratory disease. Acute and subacute neurological complications of SARS-CoV-2 infections are reported in up to 85% of patients, including those with severe COVID-19, but also in otherwise minimally symptomatic or asymptomatic people. As many as 65% of people with COVID-19 present with hyposmia, which is also a common premotor symptom in Parkinson’s disease. This symptom, added to the fact that parkinsonism has been reported following COVID-19, has drawn the attention of the medical community to the hypothetical link between SARS-CoV-2 infection and Parkinson’s disease.
• So far, three cases of parkinsonism have been reported after SARS-CoV-2 infection. Their clinical details are important for evaluating whether or not parkinsonism is causally related with COVID-19. The three patients are relatively young (two men aged 45 and 58 years, and a woman aged 35 years). The men had hypertension and were on angiotensin-converting enzyme (ACE) inhibitors, and the younger man also had asthma, whereas the woman was healthy before the infection. In two cases (a male and the female), the sense of smell was affected. None of the male patients had a monogenic cause or known genetic predisposition for Parkinson’s disease, while genetic tests were not done for the female patient. Onset was acute in the three cases (10–32 days after COVID-19 diagnosis); one patient (the 58 year old male) developed akinetic rigid syndrome in the context of a complex neurological presentation compatible with encephalopathy, including myoclonus and opsoclonus, while the other two patients had pure asymmetric akinetic-rigid features, with tremor, and mild respiratory disease. Spontaneous improvement was reported in this patient, with no response to an acute challenge with apomorphine; the female patient responded to short-term levodopa treatment, while the younger male patient had some improvement after treatment with a dopamine agonist and anticholinergics. Functional nigrostriatal neuroimaging was abnormal in all three cases, which implies dopaminergic nigrostriatal impairment, but is not diagnostic of Parkinson’s disease.
• The uncertainty about the neurological status of these patients pre-infection is a crucial issue regarding the possibility that their cases would reveal the unmasking of underlying preclinical Parkinson’s disease. In the reports of two of the cases (the male patients), the authors explicitly state that they had no history of rapid eye movement (REM) sleep behaviour disorder or hyposmia prior to the infection. The acute onset and the association with SARS-CoV-2 infection raise the possibility that these cases might represent a post or para-infectious parkinsonian syndrome, as previously reported after other viral infections. Therefore, the evidence from these three cases is too limited to link the SARS-CoV-2 infection with the development of Parkinson’s disease.
• The occurrence of transient or permanent parkinsonism following a viral infection is well known. In these cases, parkinsonism might occur through different mechanisms: 1) structural and functional basal ganglia damage mainly involving the substantia nigra pars compacta and nigrostriatal dopaminergic projection; 2) extensive inflammation or even hypoxic brain injury within the context of an encephalopathy; 3) unmasking of underlying but still non-symptomatic Parkinson’s disease; or 4) the hypothetical possibility that a viral infection might trigger a series of processes that result in the development of Parkinson’s disease over the long term in individuals with genetic susceptibility. In each of these instances, there are fundamental clinical and anatomopathological differences (figure).

Figure — The relationship between SARS-CoV-2 infection and parkinsonism

• Thus, patients in whom scenarios 1 and 2 apply will present with neurological manifestations generally incompatible with the diagnostic criteria for Parkinson’s disease, such as acute onset, myoclonus, cerebellar or pyramidal signs, and scarce or no response to levodopa treatment. Individuals in whom an infection or other noxious event unravel an underlying Parkinson’s disease are commonly seen in clinical practice, and are usually easy to recognise by the acute or sub-acute presentation of their motor features. The intriguing scenario that SARS-CoV-2 could lead to Parkinson’s disease in the long term deserves further discussion. This possibility has also been suggested in the past for other viral infections, but is now of particular concern given the high infectivity of SARS-CoV-2 and population ageing.
• Following the 1918 flu pandemic, as described by Von Economo, many patients developed parkinsonism acutely or after a delay of months or even years after encephalitic illness, accompanied or preceded by oculogyric crisis, pupillary disturbances, alteration of sleep cycles, psychiatric symptoms, and corticospinal tract signs. However, this association is not without controversy, as several cases had apparently been reported 1 or 2 years prior to the influenza pandemic. Furthermore, serum and CSF tests for 17 different arboviruses in cases of parkinsonism post-encephalitis lethargica did not differ from controls. Case reports in the late 1970s, similar to those initially reported by Von Economo, raised again the hypothesis of a causal relationship. The neuropathological assessment of some of these patients with parkinsonism post-encephalitis showed extensive bilateral loss of neurons in the substantia nigra and locus coeruleus. Lewy bodies were not observed, but glial scars were seen. Slight demyelination of the mid portion of the cerebellar peduncles was detected, and neurofibrillary tangles were observed in the brain stem and striatum in the absence of neuritic plaques. Importantly, these findings are not typical of Parkinson’s disease pathology by today’s standards. Hence, this classic example of a respiratory virus associated with damage of the substantia nigra triggered a condition clearly different from Parkinson’s disease, both clinically and pathologically.
• Some strains of influenza, such as H5N1 and H1N1, are neurotropic in mammals, and H1N1 preferentially targets the substantia nigra. H5N1-infected poultry showed abnormal postures and an inability to initiate movement. In mice, H5N1 spreads to the brain along olfactory routes or the trigeminal vagal and sympathetic nerves following intranasal instillation. In two case reports of people infected with H5N1, the authors reported seizures and rapid encephalopathy, followed by coma. In animal models, influenza viruses can also cause long-term behaviour disturbances and altered gene expression by a so-called hit and run mechanism, which suggests that multiple hits (ie, respiratory viral infections) might act as risk factors for Parkinson’s disease development, adding to the risk attributed to other factors that can occur through life.
• The neuroinvasivity of SARS-CoV-2 has been suspected on the grounds of the detection of viral RNA in the CSF of one patient with COVID-19-associated encephalopathy. Besides, in a neuropathological study of patients who died after COVID-19, SARS-CoV-2 was detected in the brains of 21 (53%) of these patients. However, the failure to detect SARS-CoV-2 in CSF in most patients with COVID-19-related encephalitis, despite evidence of brain inflammation, suggests immune-mediated mechanisms in the absence of direct virus invasion.
• A disrupted blood–brain barrier due to the cytokine storm and virus-activated lymphocytes crossing the blood–brain barrier to access the CNS in a so called Trojan horse mechanism have been suggested as possible routes of viral CNS invasion. Translational models also suggest an olfactory route into the CNS, with further transport along axons and neuron-to-neuron propagation towards the brainstem. At the cellular level, ACE2 receptors have proved crucial for SARS-CoV-2 tropism, as they are used by the virus to infect the cell. ACE2 receptors are expressed in neurons, astrocytes, and oligodendrocytes in the substantia nigra and olfactory bulb, among other brain regions, which could explain the cases of hyposmia. However, unlike in Parkinson’s disease, hyposmia is reversible in the majority of cases with COVID-19, and whether or not it reflects the ability of the virus to reach the nigrostriatal pathway remains speculative as there is no direct connection between the olfactory bulb and the substantia nigra in primates. Thus, we could perhaps conclude, on the basis of the limited evidence, that SARS-CoV-2 enters the CNS, but no data support a preferential tropism for the substantia nigra.
• The causal association of SARS-CoV-2 infection with the development of Parkinson’s disease is therefore not supported by robust evidence yet. Although the potential neurological sequelae of this novel coronavirus should not be underestimated, we are concerned about unjustified claims anticipating a future high incidence of Parkinson’s disease, secondary to the SARS-CoV-2 pandemic. A coordinated international effort to investigate viral effects is essential, and should be based on well-designed prospective studies. Rather than speculation, the obtention of robust data is warranted.
• Living with Parkinson’s does not put you at a higher risk of contracting COVID-19, but it does make it harder for you to recover if you contract it. This is because people with PD have slight differences in their immune systems.
• Parkinson’s and care partners should take these tips into consideration to be better prepared for COVID-19:

Everyday Precautions

• Wash your hands. Wash them often with soap and water for at least 20 seconds.
• Carry hand sanitizer. When in public spaces use an alcohol-based hand sanitizer that contains at least 60% alcohol.
• Sanitize around you. Stay as healthy as possible and use disinfectant wipes in public areas.
• Know the symptoms. Primary symptoms include mild to severe respiratory illness with fever, cough and/or shortness of breath.
• Avoid touching your eyes, nose and mouth with unwashed hands.
• Stock up on essential supplies.
• Practice social distancing (also known as physical distancing) as an everyday precaution. Stay six feet away from others.
• Wear a cloth face covering or surgical mask in public settings. The CDC advises the use of simple cloth face covering (or making your own) to slow the spread of the virus.
• Limit outings. If you must go out in public for essentials, practice social distancing, avoid crowded areas, wear a face mask and wash your hands often.
• During a COVID-19 outbreak in your community, stay home as much as possible to reduce your risk of being exposed.
• Avoid cruise travel and all non-essential travel.

PD Preparedness

• Check all your medications. Take inventory of all medications and reorder any that are running low.
• Write your medication list down. Write down or print a list of all your medications (not just PD medications). Include medication name, strength, times taken and dosages. This customizable medication schedule can help.
• Make a list of your doctors. Make a list of your doctors and their contact information and take it with you in the event of a hospitalization.
• Stock your Aware in Care kit in the event you need to educate a health care professional about your PD needs. Order one here.
• Have your Medical Alert Card handy. Keep it with you at all times. Print one here.
• PD Hospitalization and Coronavirus Preparedness Fact Sheet:Download this document that has crucial information for healthcare professionals in the case you are hospitalized during the COVID-19 outbreak.
• Parkinson’s Disease Care Partner Guide: Download this document that provides answers to questions for people who have loved ones in a senior living facility during the COVID-19 crisis.
• Know your community response plan. Check in with your state’s emergency management agency here.

When will there be a cure for Parkinson’s?

• Parkinson’s is the fastest growing neurological condition in the world. And currently there’s no cure. But we’re close to major breakthroughs. By funding the right research into the most promising treatments, we can get closer to a cure.

How close are we to a cure for Parkinson’s?

• We’re pushing to deliver a new treatment for Parkinson’s by the end of 2024. And we’re determined to develop a cure in the shortest possible time.
• We’ve already made vital discoveries that have revolutionised our understanding of Parkinson’s and the brain.
• Now’s the time to keep the momentum going. Together, we can find a cure.

What we know so far

• We’ve uncovered clues to the causes and genetic involvement in Parkinson’s.
• We’re figuring out the chain of events that leads to the damage and loss of brain cells.
• We’re working to advance new treatments and therapies.
• We’re exploring repurposing drugs to help manage some of the more distressing symptoms, like hallucinations and falls.
• And we know that, although people with Parkinson’s share symptoms, each person’s experience of the condition and response to treatment is different.
• Now, the science is ready for us to develop the new treatments and cure that people with Parkinson’s so desperately need.
• Research takes time. But we launched the Parkinson’s Virtual Biotech to speed up the most promising potential treatments. The more we can invest, the sooner we’ll get there.

What will a cure for Parkinson’s look like?

• Because Parkinson’s varies so much from person to person, there may not be a single ‘cure’.
• Instead we may need a range of different therapies to meet the needs of the individual and their specific form of the condition.

This mix may include treatments, therapies and strategies that can:

• slow or stop the progression of the condition
• replace or repair lost or damaged brain cells
• control and manage particular symptoms
• diagnose Parkinson’s at the earliest possible stage.

And this could involve medical treatments, such as drugs and surgical approaches, as well as lifestyle changes, for example to diet and exercise.

What new treatments are we developing?

• Thanks to the progress we’ve already made, new treatments are being tested in clinical trials that have the potential to slow, stop or even reverse Parkinson’s.

These include:

• stem cell therapies, which aim to use healthy, living cells to replace or repair the damage in the brains of people with Parkinson’s
• gene therapies, which use the power of genetics to reprogramme cells and change their behaviour to help them stay healthy and work better for longer
• growth factors (like GDNF), which are naturally occurring molecules that support the growth, development and survival of brain cells.
• And we’re developing treatments that aim to improve life with the condition, including new drugs that can reduce dyskinesia.
• Research into the interactions of genes linked to Parkinson’s disease may suggest new and better treatment options. For example, ongoing research into how the Parkinson’s disease gene LRRK2 (also called LARK2) interacts with other Parkinson’s genes is leading to a better understanding of how the disease progresses — and how it might be slowed.
• One promising treatment is deep brain stimulation, or DBS. This form of therapy uses electrical stimulation in the brain to treat Parkinson’s-related movement problems, such as tremors, stiffness, difficulty in walking and slowed movement, and may be an option when medications become less effective or side effects too onerous.

How we’re speeding up the search for a cure

We believe that new and better treatments are possible in years, not decades, and we have a clear strategy for making this happen. This includes:

• backing the best and brightest minds to unlock scientific discoveries that will lead to new treatments and a cure
• accelerating the development and testing of new treatments through our Virtual Biotech
• collaborating internationally to make clinical trials faster, cheaper and more likely to succeed through the Critical Path for Parkinson’s
• tracking down drugs for other conditions which have untapped potential for Parkinson’s.

We know that the more we’re able to invest, the faster we’ll be able to deliver. So we’re working hard to raise the funds we need to drive things forward faster.

Resilience of Alzheimer’s Disease to COVID-19

• Facing the novel coronavirus disease 2019 (COVID-19), most vulnerable individuals are seniors, especially those with comorbidities. More attention needs to been paid to the COVID-19 patients with Alzheimer’s disease (AD), which is the top age-related neurodegenerative disease.
• Since it is unclear whether AD patients are prone to COVID-19 infection and progression to severe stages, we report for the first time a retrospective analysis of the clinical characteristics of AD patients with COVID-19 pneumonia.
• We conducted a retrospective cohort study of the clinical data of 19 AD patients with COVID-19 pneumonia, compared with 23 non-AD COVID-19 patients admitted at the same time to our hospital. Demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed.
• Between AD patients and non-AD patients with COVID-19 pneumonia, the pneumonia severity was not significantly different. AD patients had a higher clustering onset than non-AD patients. The median duration from symptom onset to hospitalization were shorter in AD patients than non-AD patients, indicating the former were sent to the hospital by their family or from nursing home earlier than the later. The median duration from hospitalization to discharge seemed shorter in AD patients than non-AD patients. Dementia patients seemed less likely to report fatigue. It is noticed that more AD patients might have pericardial effusion than the non-AD patients.
• AD patients with COVID-19 were in milder conditions with a better prognosis than non-AD patients. AD patients who had adequate access to healthcare showed resilience to COVID-19 with shorter hospital stays.

Conclusion

• As the number of patients with COVID-19 is increasing worldwide, it is necessary to stress on the importance of the atypical clinical presentations (including those related to the nervous system) of COVID-19 infection, since they might be the initial manifestations. Patients with COVID-19 infection should be evaluated early for neurological symptoms. Timely analysis of cerebrospinal fluid and early appropriate management of infection-related neurological complications might be the key to improve the prognosis of critically ill patients.
• Since health-care providers might under-recognize these cases with atypical presentations, and these patients may represent a hidden source of the spread of the virus, we believe that literature on this regard should be sent by the international and local health committees to all health-care providers during this COVID -19 pandemic, to make sure that all providers are well informed and aware of these cases. Moreover, awareness campaigns addressing this issue should be directed to the population.

How does the nervous system work?

• The nervous system is made up of all the nerve cells in your body. It is through the nervous system that we communicate with the outside world and, at the same time, many mechanisms inside our body are controlled. The nervous system takes in information through our senses, processes the information and triggers reactions, such as making your muscles move or causing you to feel pain. For example, if you touch a hot plate, you reflexively pull back your hand and your nerves simultaneously send pain signals to your brain. Metabolic processes are also controlled by the nervous system.
• There are many billions of nerve cells, also called neurons, in the nervous system. The brain alone has about 100 billion neurons in it. Each neuron has a cell body and various extensions. The shorter extensions (called dendrites) act like antennae: they receive signals from, for example, other neurons and pass them on to the cell body. The signals are then passed on via a long extension (the axon), which can be up to a meter long.
• The nervous system has two parts, called the central nervous system and the peripheral nervous system due to their location in the body. The central nervous system (CNS) includes the nerves in the brain and spinal cord. It is safely contained within the skull and vertebral canal of the spine. All of the other nerves in the body are part of the peripheral nervous system (PNS).
• Regardless of where they are in the body, a distinction can also be made between voluntary and involuntary nervous system. The voluntary nervous system (somatic nervous system) controls all the things that we are aware of and can consciously influence, such as moving our arms, legs and other parts of the body.
• The involuntary nervous system (vegetative or autonomic nervous system) regulates the processes in the body that we cannot consciously influence. It is constantly active, regulating things such as breathing, heart beat and metabolic processes. It does this by receiving signals from the brain and passing them on to the body. It can also send signals in the other direction — from the body to the brain — providing your brain with information about how full your bladder is or how quickly your heart is beating, for example. The involuntary nervous system can react quickly to changes, altering processes in the body to adapt. For instance, if your body gets too hot, your involuntary nervous system increases the blood circulation to your skin and makes you sweat more to cool your body down again.
• Both the central and peripheral nervous systems have voluntary and involuntary parts. However, whereas these two parts are closely linked in the central nervous system, they are usually separate in other areas of the body.

The involuntary nervous system is made up of three parts:

• The sympathetic nervous system
• The parasympathetic nervous system
• The enteric (gastrointestinal) nervous system

The sympathetic and parasympathetic nervous systems usually do opposite things in the body. The sympathetic nervous system prepares your body for physical and mental activity. It makes your heart beat faster and stronger, opens your airways so you can breathe more easily, and inhibits digestion.

• The parasympathetic nervous system is responsible for bodily functions when we are at rest: it stimulates digestion, activates various metabolic processes and helps us to relax. But the sympathetic and parasympathetic nervous systems do not always work in opposite directions; they sometimes complement each other too.
• The enteric nervous system is a separate nervous system for the bowel, which, to a great extent, autonomously regulates bowel motility in digestion.
• The nervous system is a complex network that enables an organism to interact with its surroundings. Sensory components that detect environmental stimuli, and motor components that provide skeletal, cardiac, and smooth muscle control, as well as control of glandular secretions, are coordinated in a system to compel appropriate motor responses to the stimuli or sensory inputs that have been received, stored, and processed.
• The nervous system is made up of vast neural networks; signaling within these circuits enables thinking, language, feeling, learning, memory, and all function and sensation. It is well-established that through the plasticity of existing cells our nervous systems can adapt to situations not previously encountered, but it also has been shown that neural stem cells (NSCs) are plastic and involved in creating new connections in adaptation and response to injury. NSCs play a fundamental role in development, and in the ability to respond to stimuli in the environment and injury.

Structure and Function

• The nervous system can be divided into the peripheral and central nervous systems (PNS and CNS respectively). The brain is divided into four main parts: (1) the brain stem, consisting of the medulla, pons, and midbrain; (2) the cerebellum; (3) the diencephalon, with the thalamus and hypothalamus; and (4) the cerebral hemispheres, comprised of the cerebral cortex, basal ganglia, white matter, hippocampi, and amygdalae.
• Cranial nerves III — XII arise from the brainstem, and provide sensory innervation to the head and neck, with some extension of function into the region of the trapezius muscle through the spinal accessory nerve. The medulla is a rostral continuation of the spinal cord and contains autonomic centers that control vital functions and systems involved in breathing and the maintenance of appropriate blood pressure. These centers also regulate diaphragmatic and pharyngeal reflexes. The pons is located between the medulla and midbrain and contributes to the maintenance of posture and balance, and breathing. The pons carries information from the cerebrum to the cerebellum through the corticopontocerebellar tract. The midbrain is the most rostral portion of the brainstem and is involved in ocular movement as well as visual and auditory relay pathways via the lateral geniculate nuclei and the medial geniculate nuclei respectively.
• The cerebellum lies in the posterior fossa and coordinates head and eye movements, the planning and execution of movement, and the maintenance of posture. In addition to its well-established role in motor function, the cerebellum has been shown to be a critical component of many cognitive and sensory-motor processes, including auditory pathways involved in functions such as speech recognition.
• The thalamus and hypothalamus are located between the cerebral hemispheres and the brain stem. The thalamus is a major processing region for sensory information going to the cerebral cortex and motor information traveling in the opposite direction toward the brainstem and spinal cord. The hypothalamus controls pituitary gland secretions by secreting hormones into the hypophysial portal blood that either stimulate or inhibit the release of anterior pituitary hormones. The secretions of the posterior pituitary, which include antidiuretic hormone and oxytocin, are also controlled by cell bodies located in the hypothalamus.
• The basal ganglia or basal nuclei include the putamen, caudate, globus pallidus, ventral striatum, ventral pallidum, substantia nigra, and subthalamic nucleus. These nuclei receive input from nearly the entire neocortex and then project through basal ganglia-thalamocortical circuits to a relatively small part of the frontal lobe to aid in movement regulation. The hippocampus primarily is involved with memory, and the amygdala processes emotional information into effects on the autonomic system through the hypothalamus and hormone secretion. The cerebral cortex is largely involved in perception and higher motor function through the processing of sensory information and the integration of motor functions. The cortex contains primary, secondary, and tertiary sensory and motor areas. Cortical function centers around its ability to integrate diverse signals and provide direction in response.
• The spinal cord is the caudal extension of the CNS. The spinal cord is segmented, as is the spinal column, and projects 31 pairs of spinal nerves (with afferent and efferent components). There are eight pairs of cervical spinal nerves, 12 pairs of thoracic nerves, five pairs of lumbar nerves, five pairs of sacral nerves, and one pair of coccygeal nerves. The afferent nerves comprise the sensory nerves and carry information from the skin, joints, muscles, and visceral organs; while the efferent nerves comprise the motor nerves, both somatic and autonomic, and innervate skeletal, cardiac, and smooth muscle, as well as glandular tissue and secretory cells. The spinal cord is responsible for transmitting signals between the periphery and the rest of the CNS through both ascending and descending pathways. Due to unequal growth during development, the spinal cord is shorter than the spinal column, with the cell bodies of the spinal nerves ending around the level of L1/L2 at the conus medullaris. A structure called the cauda equina, which consists of spinal nerves L2 through C1, continues caudally in the lumbar cistern ( subarachnoid space) as the spinal nerves leave the spinal column at their respective levels. This subarachnoid space devoid of the spinal cord enables the safe performance of lumbar punctures typically between the vertebral bodies of L3 and L4, or L4 and L5.
• Impulse transmission throughout the nervous system is conducted via neurons employing synaptic connections. Consequently, there are both electrical and chemical components involved in signal transmission. A variety of neurotransmitters are used in various synapses, neuroeffector, and neuromuscular junctions; examples include acetylcholine, norepinephrine, dopamine, serotonin, glutamate, gamma-aminobutyric acid (GABA), neuropeptides, hormones, and even nitric oxide. Ion concentrations also play a significant role in impulse generation and conduction. It is of consequent importance that healthy ion balances be maintained by using active transport. The heavy use of Na+/K+-ATPase accounts for the neural demand for glucose. It has also been shown that calcium is necessary for excitation at neuromuscular junctions and ganglionic synapses and that magnesium inhibits excitability.

Embryology

• The formation of the nervous system begins with the process called neurulation which follows gastrulation and results in the development of the neural tube. During week three of development, the notochord secretes signaling factors to induce the transformation of the overlying ectoderm to neuroectoderm and the formation of the neural plate. Through folding and closure of the neural folds, the neural tube is formed. In the formation of the spinal cord, the basal plate, largely expressing Sonic hedgehog (Shh), induces the differentiation of motor areas ventrally, and the alar plate, primarily expressing bone morphogenic proteins (BMPs) and Wnt factors, induces sensory area formation dorsally. It should be noted that these signaling factors induce appropriate development along a concentration gradient with the involvement of modulating factors and other signaling factors unmentioned here; the plates and their effects are not segregated.
• The cranial parts of the CNS are formed from the prosencephalon, mesencephalon, and rhombencephalon (cranial to caudal) which are present during week four of development. In week five, the prosencephalon develops into the telencephalon and diencephalon, and the rhombencephalon becomes the metencephalon and myelencephalon. The telencephalon will ultimately become the cerebral hemispheres and basal nuclei; the diencephalon will develop into the thalamus, hypothalamus, and retinas; the mesencephalon will give rise to the midbrain, including superior and inferior colliculi; the metencephalon will become the pons and cerebellum; the myelencephalon will form the medulla.

Nerves

• Some of the largest nerves in the body include the sciatic nerve, the femoral nerve, the obturator nerve, the median nerve, the ulnar nerve, the radial nerve, and the musculocutaneous nerve. The sciatic nerve is the largest in the body and is divided into tibial and fibular parts, the distal extensions of which become the tibial and common fibular (peroneal) nerves. The common fibular nerve splits into the deep and superficial fibular nerves. The sciatic nerve innervates the posterior compartment of the thigh. The tibial nerve innervates the posterior compartment of the leg. The fibular nerves innervate the anterior and lateral compartments of the leg.
• The brachial plexus derives the nerves of the upper limb. The median nerve primarily innervates the lateral portion of the antebrachium and hand, and the ulnar nerve innervates the medial portion. The radial nerve and its branches innervate the posterior of the entire arm and hand. The musculocutaneous nerve innervates the elbow flexors and provides sensory innervation to the lateral antebrachium.

Surgical Considerations

The specialty involved in the surgery of pathologies involving the CNS is neurosurgery.

Clinical Significance

• Many neurological conditions affect the CNS. They range dramatically in scope, impact, and nature of the effect. Some conditions can lead to progressively impaired movement such as in Parkinson disease. Huntington chorea and hemiballismus cause excessive movement among other symptoms. The demyelination in multiple sclerosis can cause acute attacks, and over time, chronic degradation of function. Others may impact cognition such as the various dementias. Epilepsy can cause uncontrolled excitation. Headaches often impair the daily function of patients. Traumatic injuries can cause plegia or paresis and may result in any number of deficits depending on the location and extent of the lesion.

Smart Ways to Keep Your Central Nervous System Healthy

A complex network of sensory nerves, the nervous system is one of the crucial parts of the human body. It is responsible for reacting to both, internal and external stimuli through a number of physical actions and for carrying out many vital bodily functions as well. These typically include, taking care of digestion, beating of the heart, responding to pain, regulating breathing, emotions, body temperature, maintaining body’s posture and even strengthening the body to survive the day-to-day pressure and enjoy a better quality of life.

Typically quoting, the central nervous system is able to perform such essential functions with the help of nerves and cells that carry messages from the brain and spinal cord to the rest of the body and vice versa. When the activities of these nerves and cells are disrupted, the central nervous system fails to perform its basic functions. To avoid suffering from any CNS diseases and conditions, it is essential that you adopt smart ways to keep it healthy and in shape.

Steps to keep your Nervous System healthy

Step 1: Exercise on a daily basis

• Exercising doesn’t really mean that you need to get out and start running. It simply means to pick up a crossword puzzle and put your brain to work for the next 10 minutes. This smartly activates your nervous system and makes it perform essential functions. Neurologists suggest that taking up such activities actuates the nerve receptors to respond to even the slightest of actions and aids in fighting conditions like paralysis, stroke, memory loess, etc. It further helps in adding flexibility, resilience and sharpens ones memory.

Step 2: Get plenty of sleep

• Sleep plays a vital role in enhancing your mental health, physical health, and safety. If you do not take a proper sleep, i.e. a minimum of eight hours of sleep, you might develop some chronic conditions which may affect the way you think, react, learn, and converse with others. Sleep helps the central nervous system work properly. Moreover, a regular sleep schedule aids in learning and remembering information much more easy and convenient. Sleep disorders can put you at a risk of developing diabetes, heart failure, high blood pressure, cholesterol trouble, etc.

Step 3: Expose your body to sunlight

• Studies have shown us that sun reduces the risk of suffering a broad range of health conditions. It is one of the best ways of fortifying the health of the central nervous system. Exposing yourself to the sunlight every morning for about 10 minutes is enough to boost your body’s nervous system, and at the same time, obtain enough vitamin D.

Step 4: Add meditation in your daily routine

• Meditating is a smart way of calming and soothing your nerves. Nerves are responsible for the functioning of voluntary conscious responses and involuntary responses. Meditation help regulate your heart rate, blood pressure levels, breathing rate and calming all other sympathetic nerves.

Step 5: Walk barefoot

• In modern day living, we have forgotten the most beneficial thing that can help the body connect with the earth. Strolling barefoot is the most significant instinct for mankind. This can aid nervous system and improve your health as well as physiology. Walking barefoot can further help in improving your sleep and strengthening your immune system. Some of the other benefits are:
• Reduce pain and inflammation
• Reduce the risk of heart disease
• Normalize biological rhythms
• Increase your senses
• Improves overall posture
• Influence the brain
• Lessen the severity of menstrual cramps

Step 6: Drink green tea

• Having a cup of Green Tea at least once a day, is a great way of maintaining the heart of your nervous system. Rich in amino acid, Green Tea helps with serotonin levels. Besides, caffeine in green tea aids in increasing concentration, thinking ability and focusing. It is also a great way of treating insomnia, diabetes and Parkinson’s disease.

Step 7: Food you eat matters

• Eating a healthy diet not only aids in maintaining a proper weight and steering away a plethora of lifestyle diseases in check, but also in keeping the central nervous system in check. Foods like chia seeds, salmon, cauliflower, sardines, sprouts and canola oil are known to improve nerve transmissions. Adding them in your diet is an ideal option. Chocolates, almonds and brown rice are also highly recommended. Some other food that play a key role in strengthening your nervous system are beans, potatoes, banana, eggs and beef liver.

Additional tips:

• Drink plenty of water as dehydration is not good for the nervous system
• Put your body to exercise in order to maintain good nerve activities and function
• Excess consumption of alcohol and smoking are harmful for the nervous system
• Get your blood pressure checked regularly
• Learn new ways to increase your attention
• Make certain you intake adequate amount of healthy fats
• Keep your weight in check and reduce in case you’re obese
• Use prescribed medicines
• Taking up some healthy breathing exercise is also beneficial in maintaining the health of the nervous system.
• Protect yourself from traumatic situations
• Get plenty of sleep every day
• Eat small meals at regular intervals
• Consume adaptogenic herbs
• Decrease the intake of caffeine rich drinks

Your nervous system demands and deserves as much attention as other parts of the human body. By adhering to these above mentioned step, you can easily maintain a healthy nervous system and even steer away from a plethora of lifestyle as well as chronic diseases.

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